The long-term goal of this project is to elucidate the molecular mechanism(s) controlling the phagocytic process of the pathogenic fungus Cryptococcus neoformans (Cn) by host alveolar macrophages (AMs). Understanding these regulatory mechanisms will reveal new therapeutic strategies for the attenuation of the disease process. Cn is an opportunistic and facultative intracellular fungal pathogen that infects humans via the respiratory tract. Dissemination of the infection leads to development of a life-threatening meningo-encephalitis, particularly in immunocompromised patients. Phagocytosis of Cn by AMs represents the first line of defense by the host, and the killing of the organism is controlled by an efficient host-cell response. However, in conditions of cellular immune deficiency, phagocytosis may become detrimental for the host because Cn can grow and disseminate within macrophages. Thus, internalization of Cn by phagocytic cells may be considered either an obstacle or an opportunity for disease development, and fungal factors that control the phagocytic process may assume a crucial role in the outcome of the infection. We identified a novel cryptococcal gene encoding for an antiphagocytic protein 1 (App1), which inhibits phagocytosis of Cn by AMs. A Cn mutant lacking App1 is less pathogenic in a mouse model with a functional host-cell response but, intriguingly, more pathogenic in mice with impaired host-cell response compared to Cn wild-type strain. These observations lead us to hypothesize that App1 modulates pathogenicity of Cn through the regulation of phagocytosis by AMs. This hypothesis will be tested by the following Specific Aims: 1) Determine the mechanisms by which App1 regulates phagocytosis, and 2) determine the role and function of Ap1 in the outcome of cryptococcosis. These studies will produce new insights into the mechanisms of pathogenicity of C. neoformans at the host-microbe interface. Importantly, these studies will potentially provide new therapeutic approaches to better control the development of cryptococcal infection. Cryptococcus neoformans is an environmental microorganism that causes the most common fungal meningo-encephalitis worldwide. The pathologenesis of this fungal pathogen is not well understood. This proposal focuses on a better understanding of the pathogenic process, providing new insights into the development of better therapeutic strategies against this life-threatening fungal brain infection